Elsevier

Experimental Neurology

Volume 209, Issue 2, February 2008, Pages 321-332
Experimental Neurology

Review
The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury

https://doi.org/10.1016/j.expneurol.2007.06.020Get rights and content

Abstract

The failure of axons to regenerate after spinal cord injury remains one of the greatest challenges facing both medicine and neuroscience, but in the last 20 years there have been tremendous advances in the field of spinal cord injury repair. One of the most important of these has been the identification of inhibitory proteins in CNS myelin, and this has led to the development of strategies that will enable axons to overcome myelin inhibition. Elevation of intracellular cyclic AMP (cAMP) has been one of the most successful of these strategies, and in this review we examine how cAMP signaling promotes axonal regeneration in the CNS. Intracellular cAMP levels can be increased through a peripheral conditioning lesion, administration of cAMP analogues, priming with neurotrophins or treatment with the phosphodiesterase inhibitor rolipram, and each of these methods has been shown to overcome myelin inhibition both in vitro and in vivo. It is now known that the effects of cAMP are transcription dependent, and that cAMP-mediated activation of CREB leads to upregulated expression of genes such as arginase I and interleukin-6. The products of these genes have been shown to directly promote axonal regeneration, which raises the possibility that other cAMP-regulated genes could yield additional agents that would be beneficial in the treatment of spinal cord injury. Further study of these genes, in combination with human clinical trials of existing agents such as rolipram, would allow the therapeutic potential of cAMP to be fully realized.

Section snippets

Myelin-associated inhibitors

Cajal was the first to propose that the central nervous system (CNS) environment limits axonal regeneration after injury, but only recently has CNS myelin been identified as a major factor contributing to regenerative failure. In 1988, the laboratory of Martin Schwab provided the first direct evidence that CNS myelin contains proteins that inhibit axonal growth. In their first study, 35 and 250 kDa protein fractions were isolated from CNS myelin and these were subsequently shown to inhibit

Cyclic AMP analogues

Because MAG, Nogo and OMgp signal through a common pathway, pharmacological inhibition of PKC, Rho and ROCK is a logical strategy to promote axonal regeneration. However, it is also possible to manipulate the neuron at the molecular level so that it no longer responds to myelin inhibitors. This approach is derived from the observation that MAG is initially permissive to neurite outgrowth and only becomes inhibitory beyond a specific developmental time point. When P1 DRG neurons are plated on

cAMP-mediated axonal regeneration in models of spinal cord injury

The therapeutic potential of cAMP was recently assessed in three independent studies of spinal cord injury, each using different injury models and methods of increasing cAMP. In two of these studies, cAMP elevation was accomplished by inhibiting PDE4 activity with rolipram. PDE4 is the major source of phosphodiesterase activity in the CNS (Iona et al., 1998), making it a logical target for therapeutic intervention, and rolipram is a specific PDE4 inhibitor (Krause and Kuhne, 1988). It also has

Future directions

Many promising treatments have resulted from the identification of cAMP as a modulator of axonal regeneration, but of all the agents that have been tested to date, rolipram has shown the greatest potential. Arguably the most significant finding of the study by Pearse and colleagues (2004) was that acute administration of rolipram alone significantly improved axonal integrity and functional outcome. The fact that a single agent could so dramatically impact functional recovery after spinal cord

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